Drug delivery devices for setting and dispensing a single or multiple doses of a liquid medicament are as such well-known in the art. Generally, such devices have substantially a similar purpose as that of an ordinary syringe.
Drug delivery devices, in particular pen-type injectors have to meet a number of user-specific requirements. For instance, with patient's suffering chronic diseases, such like diabetes, the patient may be physically infirm and may also have impaired vision. Suitable drug delivery devices especially intended for home medication therefore need to be robust in construction and should be easy to use. Furthermore, manipulation and general handling of the device and its components should be intelligible and easy understandable. Moreover, a dose setting as well as a dose dispensing procedure must be easy to operate and has to be unambiguous.
Typically, such devices comprise a housing or a particular cartridge holder, adapted to receive a cartridge at least partially filled with the medicament to be dispensed. The device further comprises a drive mechanism, usually having a displaceable piston rod which is adapted to operably engage with a piston of the cartridge. By means of the drive mechanism and its piston rod, the piston of the cartridge is displaceable in a distal or dispensing direction and may therefore expel a predefined amount of the medicament via a piercing assembly, which is to be releasably coupled with a distal end section of the housing of the drug delivery device.
The medicament to be dispensed by the drug delivery device is provided and contained in a multi-dose cartridge. Such cartridges typically comprise a vitreous barrel sealed in distal direction by means of a pierceable seal and being further sealed in proximal direction by the piston. With reusable drug delivery devices an empty cartridge is replaceable by a new one. In contrast to that, drug delivery devices of disposable type are to be entirely discarded when the medicament in the cartridge has been completely dispensed or used-up.
With such multi-dose drug delivery devices at least a last dose limiting mechanism is required to inhibit setting of a dose exceeding the amount of medicament left in the cartridge. This is to avoid a potentially dangerous situation for the user believing that a set dose is entirely injected.
There already exist some drug delivery devices with end-of-content mechanisms or last dose mechanisms.
Document WO 2004/007003 A1 for instance discloses an end-of-content arrangement for preventing a dose setting member of an injection device to be set to a dose larger than the medicament remaining in the injection device. There is described a dose setting and injecting mechanism featuring an arm flexibly hinged to a coupling ring. Said arm is equipped with a cam engaging a spiral-shaped track provided on a driver. When a dose setting member and the coupling ring is rotated in a clockwise direction during the setting of a dose, the cam on the arm is moved along the track in an outward direction whereas the cam, during injection, due to the concomitant rotation of the coupling ring and the driver remains in its position in the track obtained during the dose setting.
The length of the spiral track is synchronised with the content in the cartridge such that the cam is guided out through the track opening when the cartridge is almost empty.
With many of these known approaches the last dose limiting mechanism is located rather remote from an actuation member, such like a dose dial member, by way of which the user may interact with the drive mechanism, e.g. for setting and/or dispensing of a dose. For limiting or delimiting a dose setting procedure, the angular momentum or driving force exerted by a user of the device has to be transferred from the actuation member almost through the entire drive mechanism and the plurality of its mutually interacting components until the last dose limiting mechanism is eventually activated and blocks a further dose incrementing movement of the drive mechanism and of its various components.
Since the mechanically interacting components of a drive mechanism are always subject to inevitable mechanical tolerances, a respective tolerance chain extending between the actuation member, e.g. a dose dial, and the last dose limiting mechanism may be fairly long. In effect, once a last dose limiting mechanism is activated and actually inhibits a dose incrementing displacement of e.g. a drive sleeve relative to a housing or relative to a piston rod, the locking or blocking of e.g. the drive sleeve has to propagate and to be transferred or returned to the dose dial member. Also here, due to the tolerance chain at least a minimal displacement, e.g. a rotation of the dose dial member may still be possible even though a dose incrementing displacement of the drive mechanism is effectively blocked.
Apart from such a last dose limiting mechanism it may be also required to provide a single dose limiting mechanism by way of which the maximum size of a dose to be set and dispensed can be limited to a predefined maximum.
It is therefore an object of the present invention to avoid disadvantages of known drug delivery devices and to provide a drive mechanism for a drug delivery device allowing for an intuitive operation, both for setting and for dispensing of a dose.
It is another object of the present invention to provide a drive mechanism for a drug delivery device for setting and dispensing of a dose of a medicament typically provided in a cartridge, wherein the drive mechanism is equipped with a single dose limiting mechanism and with a last dose limiting mechanism.
It is a further object to provide a drug delivery device comprising such a drive mechanism and comprising a cartridge sealed with a piston to become operably engaged with a piston rod of such drive mechanism.
In a first aspect a drive mechanism for a drug delivery device is provided for dispensing of a dose of a medicament. The drive mechanism comprises an elongated housing extending in an axial direction. Preferably, the housing is of substantially tubular or cylindrical shape that allows gripping and operating of the drive mechanism or of the entire drug delivery device by one hand of a user.
The drive mechanism further comprises a piston rod to operably engage with a piston of a cartridge containing the medicament to be dispensed by the drive mechanism. The cartridge comprises a piston, which, by means of a displacement in axial distal direction, serves to expel an amount of the medicament from the cartridge that corresponds to the axial displacement of the piston. The piston typically seals the cartridge in axial proximal direction. The piston rod serves to displace the piston of the cartridge in an axial distal direction. The piston rod is therefore operable to apply distally directed thrust or pressure to the piston of the cartridge for displacing the same in distal direction for a predetermined distance that corresponds to a respective amount of the medicament to be dispensed.
The drive mechanism further comprises at least one drive sleeve extending in axial direction and being rotatably supported in the housing. The drive sleeve is operably releasable from the piston rod for setting of a dose. Hence, during a dose setting procedure, the piston rod remains substantially stationary with respect to the housing while the drive sleeve, operably disconnected and released from the piston rod, is rotatable relative to the housing and hence relative to the piston rod.
Additionally, the drive mechanism comprises a dose setting member rotatably supported on a side wall portion of the housing and being rotatable with respect to an axis extending in radial direction with respect to the axially elongated housing. Hence, the dose setting member, typically comprising a rotatable dose dial or an actuation wheel is located on a lateral side wall portion and may be operable, hence rotatable for setting of a dose. The dose setting member and the drive sleeve are operably engageable at least for setting of a dose. Mutual engagement of the dose setting member and the drive sleeve is such that a rotation of the dose setting member with respect to the radially extending axis is transferred to a respective rotation of the drive sleeve, which is rotatably supported in the housing along the axial direction.
Arrangement of a dose setting member on a side wall portion of the housing provides an intuitive handling of the drive mechanism and the drug delivery device. Arrangement of a dose setting member on or in a side wall portion of the housing allows to spatially separate the dose setting member from a dose injection member, which is typically arranged at a proximal end of the housing and which is designed to be operated by a user's thumb. Moreover, by arranging a dose setting member on or in a side wall portion of the housing, the overall size of the dose setting member can be increased compared to an arrangement, where the dose setting member is located at a proximal end of the elongated housing.
According to another embodiment, the drive sleeve is operably engageable with the piston rod and is operably releasable from the dose setting member for dispensing of the dose.
For dispensing of the set dose, the drive sleeve is operably engageable with the piston rod. In a respective dose dispensing mode, piston rod and drive sleeve are operably engaged for that the drive sleeve may exert a driving force or driving momentum to the piston rod for driving the same in distal direction to displace the piston of the cartridge accordingly.
Typically, the drive sleeve is either operably engageable with the piston rod or with the dose setting member, depending on whether the drive mechanism is in dose dispensing or in dose setting mode. When in dose setting mode, the drive sleeve is operably engaged, hence rotatably engaged with the dose setting member while it is actually operably released from the piston rod. This way, a dose of variable size can be set by means of the dose setting member leading to a respective rotational and/or longitudinal displacement of the drive sleeve.
Typically, displacement of the drive sleeve during a dose setting procedure is accompanied by tensioning of a spring element, which is operable to return and to displace the drive sleeve in the opposite direction during a subsequent dose dispensing procedure. During such a dose dispensing procedure or in dose dispensing mode, the piston rod and the drive sleeve are operably engaged, preferably in such a way, that a rotation of the drive sleeve is transferred to a distally directed axial displacement of the piston rod for driving the piston further into the cartridge. Since the drive sleeve is operably released from the dose setting member during dose dispensing the dose setting member remains substantially stationary, e.g. for not irritating or confusing a user of the device.
According to a further embodiment, the drive sleeve is displaceable in axial direction between a proximal dose setting position and a distal dose injecting position for selectively and alternately engaging and disengaging with the piston rod and with the dose setting member. Typically, the drive sleeve is either engaged with the piston rod or with the dose setting member. In particular, when in distal dose injecting position, the drive sleeve is operably engaged with the piston rod and is operably released from the dose setting member. In the proximal dose setting position, the drive sleeve is directly operably, hence rotatably engaged with the dose setting member while it is operably released from the piston rod.
Since the drive sleeve is alternately engageable with either the piston rod or with the dose setting member, the drive sleeve serves as a kind of a clutch arrangement allowing the drive mechanism to switch between a dose setting mode and a dose dispensing mode. Moreover, switching between these two modes may be predominantly governed by the axial displacement of the drive sleeve alone between its distal dose injecting position and its proximal dose setting position. This way, a rather simple, robust and reliable clutch arrangement can be provided.
Typically, the drive sleeve encloses the circumference of the piston rod at least in an axial section. The drive sleeve is open towards the distal direction and receives or accommodates a proximal portion of the piston rod, at least in an initial device configuration. The piston rod and the surrounding drive sleeve are typically arranged concentrically. Hence, the piston rod is located in the radial centre of the drive sleeve and is co-aligned with the drive sleeve in axial direction. While the drive sleeve is rotatably supported in the housing it may only experience a limited axial displacement, e.g. for switching between the dose setting mode and the dose dispensing mode of the drive mechanism. In contrast to that, the piston rod advances in distal direction with every consecutive dose dispensing procedure. With repeated dose dispensing procedures the piston rod may therefore protrude more and more in axial direction from the drive sleeve.
According to another embodiment, the drive mechanism further comprises a dose injection member at a proximal end of the housing. The dose injection member is displaceable in axial direction between a proximal dose setting position and a distal dose injecting position. The dose injection member further distally abuts with the drive sleeve for displacing the drive sleeve into the dose injecting position. Preferably, the dose injection member extends into the housing of the drive mechanism with an axially extending shaft portion. A distal end of the shaft portion or a radially widened or radially outwardly extending abutment piece thereof abuts in distal direction and against a proximal end face of the drive sleeve.
This way, exerting a distally directed pressure to the dose injection member leads to a respective distally directed displacement of the dose injection member relative to the housing, thereby urging or pushing the drive sleeve in distal direction accordingly. In effect, the drive sleeve can be displaced from the proximal dose setting position into the distal dose injecting position by means of the dose injection member. This way, switching between a dose dispensing mode and a dose setting mode of the drive mechanism is basically operable by a simple depressing of the dose injection member in distal direction.
Additionally and according to another embodiment, the dose injection member is rotatably fixed to the housing and comprises a locking or catch member to engage with the dose setting member when reaching the dose injecting position. The locking member may comprise an arm or L-shaped beam extending radially outwardly from an axially extending shaft portion of the dose injection member. Since the dose injection member is rotatably fixed to the housing it may not rotate relative to the longitudinal axis.
Hence, the dose injection member may be only allowed to slidably move in distal and proximal direction between the above mentioned proximal dose setting position and the distal dose injection position. Since the locking member radially outwardly extends from the shaft portion of the dose injection member it may engage or may interlock with the dose setting member in such a way, that further rotation of the dose setting member relative to the housing is effectively blocked when the dose injection member is in its distal dose injecting position. Said mutual engagement of the locking member of the dose injection member with the dose setting member therefore effectively hinders the dose setting member to move or to rotate any further when the drive mechanism is in dose dispensing mode.
Hence, the locking member is therefore operable to allow a rotation of the dose setting member only when the drive mechanism is in its dose setting mode. Typically, the locking member comprises a toothed free end to engage with a gear wheel of the dose setting member in the dose injecting position, thereby inhibiting any further displacement or rotation of the dose setting member.
In another preferred embodiment, the drive sleeve is displaceable in distal direction relative to the housing against the action of a spring element axially acting between the drive sleeve and the housing. By means of the at least one spring element, the drive sleeve may return into its proximal dose setting position as soon as a distally directed thrust acting on the drive sleeve drops below a predefined threshold. In the event that a user prematurely releases the dose injection member, the drive sleeve will immediately return into its dose setting position under the effect of the tensioned spring element.
Since the drive sleeve is in axial abutment with the dose injection member also the injection member will return into its initial dose setting position as soon as a user's thumb no longer depresses the dose injection member in distal direction. The spring element may be arranged axially between a radially inwardly extending support of the housing and a respective support located on the outside of the drive sleeve.
Furthermore, the at least one spring element may be integrally formed with either the housing or with the drive sleeve. This way, a separate step of assembling the spring element between the drive sleeve and the housing can be omitted. Preferably, the spring element is located at a distal end face of the drive sleeve. It may axially extend and project against an insert fixedly arranged in the housing of the drive mechanism.
Alternatively, the spring element may also engage with the housing directly. Moreover, the insert, which is typically adapted to axially guide and to receive the piston rod, may also be integrally formed with the housing.
According to a further embodiment, the dose setting member comprises a gear wheel located inside the housing to engage with a crown wheel of the drive sleeve when in dose setting position. The crown wheel of the drive sleeve is typically located on a proximal end face of the drive sleeve while the gear wheel of the dose setting member is oriented parallel to an actuation wheel of the dose setting member extending outside the housing. The gear wheel of the dose setting member is preferably rotatable with respect to the radially extending axis of the dose setting member.
The gear wheel may be integrally formed with and may thus be integrated into the dose setting member. Since the gear wheel directly engages with a crown wheel of the drive sleeve, which may also be integrally formed with a drive sleeve, a direct mutual engagement of dose setting member and drive sleeve can be attained. This way, a tolerance chain and a mechanical path between various mutually interacting components of the drive mechanism can be kept rather short, thereby providing a direct feedback to a user and allowing for a precise setting and adjusting of a dose.
Since the gear wheel of the dose setting member directly engages with the crown wheel of the drive sleeve, the angular momentum of the dose setting member rotating around a radial axis can be directly transferred into a respective angular momentum of the drive sleeve rotating around a longitudinal axis extending in axial direction.
Hence, by the direct and mutual interaction of the dose setting member's gear wheel with the crown wheel of the drive sleeve, the direction of angular momentum inside the drive mechanism can be deflected, e.g. about 90°, from the radial direction into the axial direction.
In a further embodiment a support member is provided fixedly attached to the housing and having a radially outwardly extending socket portion to support a hollow shaft of the dose setting member. The support member is typically to be arranged into a proximal receptacle of the housing. Preferably, the support member and the housing member may be mutually fixed by means of mutually engaging grooves or latch elements, by way of which the support member can be fixed relative to the housing in axial as well as in circumferential or tangential direction.
The support member serves as a rotative support for the dose setting member. For this purpose, the support member comprises a radially outwardly extending socket portion to engage with a hollow shaft of the dose setting member. Here, the socket portion of the support member may not protrude radially from the housing. Hence, the radially outwardly extending socket portion of the support member lies completely inside the tubular housing and may flush with a through opening of the housing to be covered by the dose setting member.
Alternative to the above mentioned mutual engagement of support member and dose setting member it is also conceivable, that the support member comprises a radially inwardly extending receptacle adapted to receive a correspondingly shaped shaft of the dose setting member. Typically, the dose setting member is rotatable relative to the support member along the axis of rotation extending in radial direction. It is preferably the radially outwardly extending socket portion that forms said axis or bearing for the dose setting member. Preferably, support member and dose setting member are not threadedly engaged so that the dose setting member does not experience a radial offset when dialed, e.g. in a dose incrementing or dose decrementing direction.
According to another preferred aspect, the support member further comprises an axially extending receptacle at a proximal end to slidably receive the dose injection member. The support member, in particular its receptacle, and the dose injection member may be rotatably fixed, e.g. by means of mutually corresponding and radially extending grooves and protrusions. The dose injection member may be splined to the support member. The support member may for instance comprise at least one axially extending groove to receive a correspondingly shaped and radially extending protrusion so that the dose injection member can be slidably supported in axial direction but is rotatably fixed relative to the support member.
Preferably, rotatable fixing of support member and the dose injection member can be achieved by means of the radially outwardly extending locking or catch member of the dose injection member slidably disposed in axial direction in a correspondingly shaped axially extending groove of the support member. Preferably, said groove can be opened in proximal direction, thereby allowing to insert the dose injection member in distal direction into the support member upon assembly of the drive mechanism.
This way, the locking member provides a double function. On the one hand it serves to rotatably interlock with the dose setting member and on the other hand it inhibits a rotation of the dose injection member itself around the longitudinal axis relative to the support member. Moreover, the support member and the dose injection member are axially fixed, e.g. by means of a snap-in feature provided on the outer circumference of the axially extending shaft portion of the dose injection member. Accordingly, the support member typically comprises a recessed portion to receive, e.g. a radially outwardly extending snap- or latch element of the dose injection member.
According to a further preferred embodiment, a last dose limiting member is arranged between the socket portion of the support member and the hollow shaft of the dose setting member. Preferably, the hollow shaft as well as the socket portion comprise a circular geometry. The last dose limiting member is in particular sandwiched between the socket portion and the hollow shaft.
The last dose limiting member is furthermore engaged with the socket portion and with the hollow shaft in such a way, that a rotation of the hollow shaft, hence of the dose setting member relative to the socket portion leads to a displacement of the dose limiting member along the socket portion, hence radially inwardly or radially outwardly with respect to the overall geometry of the housing. In this context a radially directed displacement corresponds to a displacement along the longitudinal axis of the socket portion.
In particular, the last dose limiting member may be threadedly engaged with the socket portion and may be rotatably fixed and slidably displaceable relative to the hollow shaft. This way, a rotation of the hollow shaft relative to the socket portion slaves the dose limiting member around the socket portion, thereby following an outer thread of the socket portion. In this embodiment the last dose limiting member comprises a correspondingly shaped threaded portion to mate with the outer thread of the socket portion.
In an alternative embodiment, the last dose limiting member is threadedly engaged with a hollow shaft and is rotatably fixed and slidably displaceable to the socket portion. Here, an inside facing side wall of the hollow shaft is threadedly engaged with the dose limiting member while the dose limiting member is splined to the socket portion. Then, a rotation of the hollow shaft and hence of the dose setting member relative to the socket portion leads to a radially directed displacement of the dose limiting member relative to the socket portion.
Since a rotation of the dose setting member relative to the support member or relative to the housing is only allowed and possible in the dose setting mode, the last dose limiting member will be displaced relative to the hollow shaft only during dose setting or dose correcting procedures. During dose dispensing, the last dose limiting member will remain stationary since the dose setting member and hence its hollow shaft is rotatably locked and fixed by the locking member of the depressed dose injection member.
Naturally, the travel path the last dose limiting member is allowed to travel along the socket portion is adapted and correlated to the maximum distance the piston rod of the drive mechanism may advance in distal direction during consecutive dose dispensing procedures. Accordingly, the threaded engagement of the last dose limiting member and the socket portion of the support member as well as the elongation of the socket portion are designed and chosen accordingly in order to match with the size of the cartridge and the amount of medicament contained therein. Moreover, the position of the last dose limiting member relative to the socket portion of the support member is unequivocally correlated and always corresponds to the axial position of the piston rod and hence to the axial position of the piston of the cartridge operably engaged with the piston rod of the drive mechanism.
In a further preferred embodiment the last dose limiting member is displaceable along the socket portion only between a zero dose limiting stop and a last dose limiting stop. Preferably, the zero dose limiting stop as well as the last dose limiting stop radially extend from opposite end portions of the socket portion or from opposite end portions of the hollow shaft. Preferably, the zero dose limiting stop and the last dose limiting stop extend radially from the threaded socket portion or from the threaded hollow shaft of the dose limiting member, depending on how the mutual engagement of last dose limiting member, socket portion and hollow shaft is implemented.
The zero dose limiting stop as well as the last dose limiting stop typically extend radially outwardly at the end of an external threaded portion of the socket portion. In this way, a revolving motion of the last dose limiting member around the socket portion or around the hollow shaft can be blocked and delimited when the last dose limiting member gets in radial abutment with either the zero dose limiting stop or with the last dose limiting stop. Typically, after the device is assembled, the last dose limiting member disposed in abutment with the zero dose limiting stop. This way, a rotation of the dose setting member in a dose decrementing direction can be effectively blocked. Hence, in an initial device configuration, the dose setting member can only be dialed in a dose incrementing direction, thereby displacing the last dose limiting member away from the zero dose limiting stop.
In the event that the medicament in the cartridge is almost used up and when the piston of the cartridge almost reaches a distal end position, the last dose limiting member will be located proximate to the last dose limiting stop. In such a configuration, the dose setting member may be dialed in a dose incrementing direction until the last dose limiting member abuts with the last dose limiting stop. When the last dose limiting member engages with the last dose limiting stop, a further rotation of the hollow shaft and hence of the dose setting member is effectively blocked and setting of a dose exceeding the amount of medicament remaining in the cartridge can be effectively prevented.
Moreover, since the dose setting member is directly engaged with the last dose limiting member and since a rotation of the last dose limiting member relative to socket portion of the support member and hence the housing can be blocked by a last dose stop, a rather direct and robust feedback can be provided to a user of the device when the drive mechanism reaches the last dose limiting configuration.
By having the last dose sleeve in direct engagement with the dose setting member, a tolerance chain of a last dose limiting mechanism is fairly short and the negative influence of inevitable mechanical tolerances and mechanical play between various functional and mutually engaging components of the drive mechanism can be reduced to a minimum.
According to another embodiment, the drive sleeve is rotatably and axially slidably engaged with a dose indicating sleeve threadedly engaged with the inside of the housing. Preferably, the dose indicating sleeve at least partially houses the drive sleeve. In particular, in axial direction, the dose indicating sleeve is arranged at least in part around the outer circumference of the drive sleeve. The drive sleeve and the dose indicating sleeve may be splined so that a rotation of the drive sleeve is directly transferable to a corresponding rotation of the dose indicating sleeve.
The mutual engagement of the drive sleeve and the dose indicating sleeve further enables the dose indicating sleeve to slide along the drive sleeve in axial direction. Since the dose indicating sleeve is threadedly engaged with the inside of the housing, a rotation of the drive sleeve leads to a corresponding rotation of the dose indicating sleeve, which due to its threaded engagement with the housing becomes subject to a helical or screw-like motion. The outside of the dose indicating sleeve is provided with consecutive numbers indicating the amount of a dose actually set by the drive mechanism. Depending on the degree of rotation of the drive sleeve, a respective number of the dose indicating sleeve will show up in a dose indicating window of the housing.
Moreover, the dose indicating sleeve comprises at least one stop at one axial end to abut with a single dose limiting stop located on the inside of the housing. The single dose limiting stop of the housing typically extends in axial direction to allow and to support a circumferentially or tangentially acting mutual abutment of drive sleeve and housing when reaching a zero dose or a maximum dose configuration. Accordingly, the at least one stop provided at one axial end of the dose indicating sleeve extends in axial direction to get in direct circumferential or tangential abutment with the correspondingly shaped single dose limiting stop at the inside of the housing.
Irrespective on whether the drive mechanism is in dose dispensing or dose setting mode the dose indicating sleeve and the drive sleeve are rotatably fixed. Therefore, a revolving or turning motion of the drive sleeve, either for dose incrementing or dose decrementing equally transfers to a respective rotation of the dose indicating sleeve. Typically, the drive mechanism rotates in one direction, e.g. in clockwise direction during a dose setting procedure and rotates in the opposite direction, e.g. during dose injection. Accordingly, the numbers provided on the outside of the dose indicating sleeve and being visible through the dose indicating window of the housing, will count up and count down during dose setting and dose dispensing, respectively.
According to another embodiment, the drive sleeve is rotatably biased relative to the housing by means of a helical spring extending around the drive sleeve. The helical spring is coupled with one end with the drive sleeve while another end of the helical spring is preferably coupled and connected with the housing. This way, the drive sleeve is rotatably supported for setting of a dose relative to housing against the action of the helical spring.
Such rotational and spring biasing displacement of the drive sleeve is preferably accompanied and controlled by a ratchet mechanism of the drive sleeve having at least one ratchet member to engage with a toothed profile or toothed surface of the housing to prevent uncontrolled and counter-directed rotation of the drive sleeve. Typically, thee drive sleeve comprises a resiliently deformable arc-shaped ratchet member extending along the outer circumference of the drive sleeve and having a ratchet tooth or nose extending radially outwardly and mating with a correspondingly shaped toothed surface provided on the inner wall of the housing.
Alternatively, also the housing may be equipped with a radially resiliently deformable ratchet member to engage with a geared or toothed profile at the outer circumference of the drive sleeve.
This way, the drive sleeve may be stepwise rotated in a dose incrementing direction as governed by the size of the toothed surface. Moreover, a dose incrementing dialing or rotation of the drive sleeve is accompanied with an audible click-sound generated by the ratchet member meshing with the toothed profile.
Mutual engagement of the ratchet member of the drive sleeve with the toothed profile of the housing is further designed in such a way, that a user may also correct the size of a set dose, e.g. by rotating the drive sleeve in an opposite direction. However, for such a correcting and oppositely directed rotation of the drive sleeve, application of a counter-directed correction force is to be applied to the dose setting member, which is larger than a holding force provided by the mutual engaging ratchet member and the toothed surface.
Apart from application of a counter-directed correction force above a predefined force level, other dose-correcting mechanisms are also conceivable here by means of which the ratchet mechanism may be temporally overridden.
According to a further embodiment, the piston rod is threadedly engaged with a drive nut which is axially fixed to the housing and which is rotatably supported in the housing. Preferably, drive nut and drive sleeve are co-aligned around the piston rod. The drive nut may be located distally from a distal end of the drive sleeve and is preferably axially secured in the housing. The piston rod is typically splined to the housing or to an insert fixedly attached to and positioned in the housing and providing a radially inwardly extending flange or web with a through opening, through which the piston rod may extent axially.
Moreover, the drive sleeve is rotatably engaged with the drive nut when in dose injecting position and the drive sleeve and drive nut are disengaged when the drive sleeve is in its dose setting position.
It is to be mentioned here, that the insert is fixed and immobilized to the housing. The insert may be provided as a separate component to be assembled in the housing. Alternatively, insert and housing may be integrally formed. Hence, any reference made herein to the housing is equivalently valid for the housing and vice versa.
The through opening of the flange or web of the housing or of the respective insert comprises at least one radially inwardly extending protrusion that mates and engages with the at least one axially elongated groove of the piston rod. Consequently, the piston rod is rotatably fixed to the housing and is effectively hindered to rotate relative to the housing. A distally directed displacement of the piston rod relative to the housing can thus be attained by the rotating drive sleeve threadedly engaged with the piston rod.
The drive nut is preferably only free to rotate in one direction relative to the housing that corresponds to a dose setting procedure, during which the piston rod is driven in distal direction. Hence, the drive nut may be equipped with another ratchet mechanism operating in an opposite sense compared to the ratchet mechanism of the drive sleeve. The drive nut's ratchet mechanism only allows a dispensing-correlated rotation of the drive nut relative to the housing but prevents a counter-directed rotation. In a similar way, also the ratchet mechanism of the drive nut may comprise e.g. an arc-shaped ratchet member extending in tangential or circumferential direction at the outer circumference of the drive nut.
Also here, the ratchet member may comprise a ratchet tooth to resiliently engage with a correspondingly shaped toothed surface at an inside facing portion of the sidewall of the housing or of a corresponding insert.
Alternatively, the housing or insert may be equipped with a radially resiliently deformable ratchet member to engage with a geared or toothed profile at the outer circumference of the drive nut.
For dispensing of a set dose, it is intended that the drive sleeve is axially displaceable relative to the housing for rotatably engaging the drive sleeve and the drive nut. Here, a distal end or a distal face of the drive sleeve is adapted to rotatably engage with an opposite and hence proximal face of the drive nut. Drive nut and drive sleeve therefore comprise mutually corresponding and axially extending positive locking means, such like crown wheels in order to transfer angular momentum from the drive sleeve to the drive nut during a dose dispensing procedure.
Typically, the drive sleeve is biased in axial direction relative to the housing by means of one or several spring elements. If the drive sleeve after completion of a dose setting procedure is displaced against respective spring forces in distal direction, it may first rotatably engage with the drive nut and it may then consecutively rotatably disengage from the housing. The distally directed displacement of the drive sleeve may therefore disengage the ratchet mechanism by way of which the drive sleeve is rotatably locked to the housing. Once such a release configuration is obtained, the drive sleeve is free to rotate relative to the housing under the effect of the relaxing helical spring.
Since in this release configuration the drive sleeve is operably and rotatably engaged with the drive nut, the drive nut may rotate accordingly, thereby advancing the piston rod in distal direction. It is to be noted that the drive nut's ratchet mechanism operates in the opposite sense compared to the ratchet mechanism of the drive sleeve. Also here, rotation of the drive nut during dose dispensing may be accompanied by consecutive click-sounds generated by its ratchet member meshing with a correspondingly shaped toothed profile.
According to another aspect, the invention also relates to a drug delivery device for dispensing of a dose of a medicament. The drug delivery device comprises a drive mechanism as described above and a cartridge at least partially filled with the medicament to be dispensed by the drug delivery. The cartridge is arranged in the housing of the drive mechanism or in a cartridge holder of the drug delivery device which is fixed to the housing either releasably or non-releasably, e.g. in case of a disposable drug delivery device. Consequently, the drug delivery device comprises a cartridge holder to receive and to accommodate a cartridge filled with the medicament.
Apart from that, the drug delivery device and the drive mechanism may comprise further functional components, such like a dose injection member, by way of which a user may trigger and control the drug delivery device and its drive mechanism for dispensing of a dose of the medicament.
In the present context, the distal direction points in the direction of the dispensing and of the device, where, preferably a needle assembly is provided having a double-tipped injection needle that is to be inserted into biological tissue or into the skin of a patient for delivery of the medicament.
The proximal end or proximal direction denotes the end of the device or a component thereof, which is furthest away from the dispensing end. Typically, an actuating member is located at the proximal end of the drug delivery device, which is directly operable by a user to be rotated for setting of a dose and which is operable to be depressed in distal direction for dispensing of a dose.
While the axial direction typically coincides with the longitudinal direction or longitudinal elongation of the housing, the radial direction coincides with a lateral or transverse direction typically extending perpendicular to the axial or longitudinal direction. The term “drug” or “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound,
wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a proteine, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound,
wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis,
wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy,
wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4.
Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.
Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.
Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.
Exendin-4 derivatives are for example selected from the following list of compounds:
H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
des Pro36 Exendin-4(1-39),
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),
wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;
or an Exendin-4 derivative of the sequence
des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),
H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,
des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,
des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;
or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.
Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.
A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium.
Antibodies are globular plasma proteins (−150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.
The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.
There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.
Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.
In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals.
Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity.
An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H-H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv).
Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington's Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology.
Pharmaceutically acceptable solvates are for example hydrates.
It will be further apparent to those skilled in the pertinent art that various modifications and variations can be made to the present invention without departing from the spirit and scope of the invention. Further, it is to be noted, that any reference signs used in the appended claims are not to be construed as limiting the scope of the present invention.